Abstract
GPR48 can mediate keratinocyte proliferation and migration. Our investigations showed that AG1478, an inhibitor of EGFR tyrosine kinase, could block GPR48-mediated cellular processes. AG1478 treatment of Gpr48(+/+) cells also decreased phosphorylation of EGFR, ERK and STAT3. Subsequent screening using conditioned media immunodepleted of EGFR ligands identified HB-EGF as the ligand responsible for phosphorylation of EGFR, ERK and STAT3. HB-EGF was reduced in Gpr48(-/-) cell culture medium, but its addition restored the phosphorylation of EGFR, ERK, STAT3, as well as cell proliferation. Confirmation that GPR48 mediates EGFR signaling pathway through HB-EGF was subsequently performed using an inhibitor of HB-EGF.
Copyright © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Proteins / pharmacology
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Cell Line
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Cell Proliferation
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Culture Media, Conditioned / pharmacology
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ErbB Receptors / genetics*
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins / metabolism*
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Intercellular Signaling Peptides and Proteins / pharmacology
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Keratinocytes / cytology
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Keratinocytes / drug effects
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Keratinocytes / metabolism*
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Mice
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Mice, Knockout
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Protein Kinase Inhibitors / pharmacology
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Quinazolines
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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STAT3 Transcription Factor / metabolism
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Transcriptional Activation*
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Tyrphostins / pharmacology
Substances
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Bacterial Proteins
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Culture Media, Conditioned
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Hbegf protein, mouse
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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LGR4 protein, mouse
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Protein Kinase Inhibitors
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Quinazolines
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Receptors, G-Protein-Coupled
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Tyrphostins
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CRM197 (non-toxic variant of diphtheria toxin)
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RTKI cpd
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ErbB Receptors